E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029202 |
E.1.2 | Term | Nervous system disorder |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the annualized relapse rate (ARR) in subjects with RMS after 96 weeks (approximately 2 years) treatment with IV infusion of ublituximab/oral placebo compared to 14 mg oral teriflunomide/IV placebo. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to examine the effects of ublituximab/oral placebo as compared to teriflunomide/IV placebo as follows:
1.On MRI parameters,
2.The percentage with accumulation of disability,
3.Time to onset of confirmed disability progression for at least 12 weeks,
4.The percentage of subject with a relapse,
5.Time to first confirmed relapse,
6.The percentage of subjects with no evidence of disease activity (NEDA), and
7.To evaluate the safety of ublituximab/oral placebo, as determined by adverse events (AEs) and serious adverse event (SAEs), including MS worsening.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 18-55 age
2. Diagnosis of RMS (McDonald criteria 2010)
3. ≥ 2 relapses in prior 2 years or 1 relapse in the year prior to screening and/or ≥1 Gd enhancing lesion
4. Documented MRI of brain with abnormalities consistent with MS
5. Active disease
6. EDSS 0-5.5 (inclusive) at screening
7. B cell counts ≥5% of total lymphocytes
8. Neurologic stability ≥ 30 days prior to screening and baseline
9. Female subjects who are not of child-bearing potential, have documented surgical sterilization ,and female subjects of child-bearing potential who have a negative serum pregnancy test at baseline. Female subjects of child-bearing potential, and all male partners must consent to use a medically/clinically acceptable method of contraception throughout the treatment period and for 20 weeks after the cessation of active treatment. Female subjects of child-bearing potential must agree to undertake urine pregnancy tests every 4 weeks during active treatment and the follow up period.
10. Fertile male subjects participating in the study who are sexually active with women of child bearing potential, must agree to use a condom during the treatment period and for an additional 20 weeks after cessation of active treatment. Agree to use an accelerated elimination procedure for teriflunomide or oral placebo after the last dose of study medications or early termination from the study.
11. Willingness and ability to comply with trial and follow-up procedures, give written consent. |
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E.4 | Principal exclusion criteria |
1.Treatment with Anti-CD20 or other B cell directed treatment
2.Treatment with the following therapies at any time prior to randomization:
a.Alemtuzumab
b.Natalizumab,
c.Teriflunomide,
d.Leflunomide
e.Stem cell transplantation
3.Contraindications to teriflunomide or incompatibility with it's use
4.Therapies that are disallowed (min. of 4 weeks prior to randomization): phenytoin, warfarin, tolbutamide, St John’s Wort or cholestyramine
5.Prior DMT exposure within months of screening:
a.24 months with cladribine
b.6 months with daclizumab, azathioprine, methotrexate, or cyclophosphamide
c.90 days with fingolimod, or experimental S1P modulators,, IV immunoglobulin, and plasmapheresis
d.30 days with glatiramer acetate, interferons, dimethyl fumarate, or glucocorticoids
6.Diagnosed with Primary Progressive MS (PPMS)
7.Pregnant or nursing
8.≥ 10 years disease duration from onset with subjects EDSS ≤ 2.0
9.Contraindication for MRI and/or gadolinium
10.Known presence of other neurologic disorders that may mimic MS
11.Current evidence or known history of clinically significant infection including:
a.Chronic or ongoing active viral, bacterial, or fungal infectious disease requiring long term systemic treatment such as, but not limited to: PML, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, or active hepatitis C
b.Previous serious opportunistic or atypical infections
c.History of positive serology for hepatitis B or hepatitis C or HIV
12. History of clinically significant CNS trauma (e.g. traumatic brain injury, cerebral contusion, spinal cord compression)
13.History of liver disease, including but not limited to:
a.Known history of active hepatitis B or C any time prior to randomization or known history of active hepatitis A within 3 years prior to randomization
b.Presence of chronic liver or biliary disease
c.Moderate or severe hepatic impairment defined as Child Pugh Score B or C, respectively, based on measurement of total bilirubin, serum albumin, International Normalized Ratio (INR) and as well as on presence /absence and severity of ascites and hepatic encephalopathy
d.Any of the following abnormal laboratory values at screening or first infusion:
•ALT/SGPT>2X the Upper Limit of Normal (ULN)
•AST/SGOT>2X ULN
14.Previous diagnosis with a congenital or acquired immunodeficiency
15.History of renal impairment, including, but not limited to:
a.Hypoproteinemia (e.g., in case of severe liver disease or nephrotic syndrome) with serum albumin <3.0 g/dL
b.Severe renal insufficiency requiring renal dialysis
16.Past or current history of medically significant adverse effects (including allergic reactions) from:
a.Corticosteroids
b.Diphenhydramine
c.Murine or mouse/human chimeric antibodies
17.Subjects with significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia
a.Hematocrit <24% and/or
b.Absolute white blood cell count <4,000 cells/mm3 and/or
c.Platelet count <150,000 cells/mm3 and/or
d.Absolute neutrophil ≤ 1,500 cells/mm3
18.Absolute neutrophil count or platelet count outside of normal range (as per reference laboratory)
19.Absolute lymphocyte counts less than 1000/microliter
20.Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
a.Symptomatic, or history of documented congestive heart failure (New York Heart Association functional classification III-IV [see Appendix B]
b.QTcF: Female >450 msec; male > 430 msec
c.Angina not well-controlled by medication
d.Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting in the past 6 months prior to screening
21.Other significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which could affect the subject’s safety, impair the subject’s reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by the protocol, as determined by the PI of the trial
22.Current participation in any other interventional clinical trial. Participation in non-interventional trial requires approval of the protocol by study chair
23.Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol
24.Lack immunity to varicella as determined by screening. Subject may receive vaccine and be rescreened
25.Vaccination with live virus within 2 months of randomization
26.History or presence of malignancy (except for surgically excised basal or squamous cell skin lesions, lymphoproliferative disease, or history of total lymphoid irradiation or bone marrow transplantation |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is ARR defined as the number of confirmed relapsed per-subject year. The estimate of ARR for a treatment group will be the total number of relapsed for subjects in the respective treatment group divided by the sum of duration on study for subjects in that specific treatment group. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key secondary efficacy endpoints are as follows:
1.MRI parameters,
a.The total number of gadolinium enhancing (Gd-enhancing) T1-lesions per MRI scan over the treatment period
b.Volume of hypointense post-gadolinium T1 lesion component (black holes)
c.Volume of T2 lesion
d.Brain volume changes
2.The percent of subjects with no evidence of disease activity (NEDA)
a.NEDA is defined as subjects without relapses, MRI activities (no T1 Gd+ lesions and no new/enlarging T2 lesions), and no 12-week confirmed disability progression.
3.The percentage of subjects with accumulation of disability
a.Time to onset of confirmed disability progression for at least 12 weeks
b.Percent of subjects free of disability progression at 6 months, 1 year, and 2 years
4.The percentage of subjects with a relapse
5.Time to first confirmed relapse |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belarus |
Georgia |
Poland |
Russian Federation |
Serbia |
Spain |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |